EFFECTS OF CALCIUM ANTAGONIST DILTIAZEM ON LEUKOCYTE ELASTASE AND ON REACTIVE OXYGEN SPECIES PRODUCTION IN HUMAN NEUTROPHILS

• Published in: Pharmacological research Vol. 33; no. 2; pp. 117 - 122
• Main Authors: KHALFI, F., GRESSIER, B., BRUNET, C., DINE, T., LUYCKX, M., CAZIN, M., CAZIN, J.C.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.02.1996
• Subjects: cytosolic calcium; diltiazem; Diltiazem - pharmacology; Dose-Response Relationship, Drug; elastase; Humans; Leukocyte Elastase - drug effects; Neutrophils - drug effects; oxidants; Oxygen - metabolism; PKC; PMNs; elastase; PKC; diltiazem; oxidants; PMNs; cytosolic calcium
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1006/phrs.1996.0017

During inflammatory disorders, some proteases and very reactive oxygen metabolites are produced by activated phagocytic cells. These proteases and oxidants are involved in many diseases like tissue injury or atherosclerosis. It was shown in vitrothat diltiazem, a calcium channel blocker, had antielastase and antioxidant properties. This drug inhibited the release of elastase by neutrophils in a dose dependent manner when these cells were stimulated by phorbol-myristate-acetate (PMA) or by formyl-methionyl-leucylphenylalanine (fMLP) with an IC 50of 144.5 μ Mand 132.8 μ M, respectively. Towards the oxidants, the 50% inhibitory concentrations (IC 50) of diltiazem are 422 μ M, 138 μ Mand 165 μ Mfor superoxide anion, hypochlorous acid and hydroxyl radical production by PMA stimulated human neutrophils, respectively. In the case of fMLP stimulated human neutrophils, the IC 50for superoxide anion is 78 μ M. When human neutrophils were stimulated by dioctanoylglycerol (DiC8) or by calcium ionophore (Ca.I), the IC 50for superoxide anion were 175.5 μ Mand 186 μ M, respectively. When human neutrophils were stimulated by opsonized zymosan (OZ), diltiazem did not show an inhibition of superoxide production in a dose dependent manner. This drug did not act by scavenging elastase or oxidants as demonstrated by cell free models. A mechanism of elastase and oxygen metabolites inhibition by diltiazem has been considered specially toward the mobilization of cytosolic calcium and an inhibition of protein kinase C cannot be excluded. The results suggest that diltiazem might contribute to attenuate the development and the progression of atheroma where oxidants and elastase have been implicated.